Methods For Increasing Forced Expiratory Volume In Asthmatics Using Benralizumab

ABSTRACT

Provided herein is are methods of increasing forced expiratory volume in one second (FEV 1 ) in an asthma patient, comprising administering to the patient an effective amount of benralizumab or an antigen-binding fragment thereof.

BACKGROUND

More than 300 million people around the world have asthma. Despite theuse of long-acting bronchodilators and inhaled corticosteroids, asthmacontinues to be a major source of morbidity worldwide. (Masoli M, et al.Allergy 59: 469-78(2004)).

Relapse following acute asthma exacerbation has been reported to rangefrom 41 to 52% at 12 weeks despite the use of systemic steroids upondischarge (Lederle F, et al. Arch Int Med 147:2201-03 (1987)).Management of these patients has proved problematic due either to severerefractory disease or inability and/or unwillingness to comply withmedical treatment. In one study of patients admitted to the hospital,some with near fatal asthma, 50% were non-compliant with systemiccorticosteroids at 7 days following discharge (Krishnan J, et al. AJRCCM170: 1281-85 (2004)). Many factors may contribute to non-complianceincluding poor access to routine quality healthcare (particularly in theinner city), lack of education or understanding of their disease,unwillingness to accept the chronic nature of their disease, orinability to obtain medications.

Many lines of evidence implicate eosinophils as one of the maincausative cells of asthmatic airway inflammation (James A. Curr OpinPulm Med 11(1):1-6 (2005)). Peripheral blood (PB) eosinophilia is a riskfactor for relapse of acute asthma (Janson C and Herala M. Resp Med86(2):101-104 (1992)). In subjects with peripheral blood eosinophilia,the risk of dying from asthma was 7.4 (confidence interval, 2.8-19.7)times greater than in those without eosinophilia (Ulrik C andFredericksen J. Chest 108:10-15 (1995)). Necropsy results haveidentified 2 distinct pathogenic inflammatory mechanisms of fatal asthma(Restrepo R and Peters J. Curr Opin Pulm Med 14: 13-23 (2008)). Aneutrophilic infiltrate is more prominent in those dying suddenly(approximately within 2 hours on onset of symptoms), while aneosinophilic infiltrate is more common in those dying from moreprotracted asthma crises. Sputum and blood eosinophils can also beincreased in patients presenting to the ED with rapid onset of asthmasymptoms (Bellido-Casado J, et al. Arch Bronconeumol 46(11): 587-93(2010)). Therapies that target eosinophils lead to a reduction in thenumber and severity of asthma exacerbations as compared to the use ofclinical guidelines (Green R, et al. Lancet 360:1715-21 (2002); HaldarP, et al. NEJM 360:973-84 (2009)).

Benralizumab (MEDI-563) is a humanized monoclonal antibody (mAb) thatbinds to the alpha chain of the interleukin-5 receptor alpha (IL-5Rα),which is expressed on eosinophils and basophils. It induces apoptosis ofthese cells via antibody-dependent cell cytotoxicity. A singleintravenous (IV) dose of benralizumab administered to adults with mildasthma provoked prolonged PB eosinopenia likely due to the effects oneosinophil/basophil bone marrow progenitors that express the target(Busse W, et al. JACI 125: 1237-1244 e2 (2010)). In addition, a singledose of benralizumab significantly reduced the blood eosinophil count insubjects who presented to the emergency department with a severe asthmaexacerbation, but did not impact pulmonary function (WO 2013/066780).

Thus, given the high unmet need of increasing lung function, e.g., asmeasured by forced expiratory volume in one second (FEV₁), in patentswith asthma and that some patients with asthma have an eosinophiliccomponent, the effect of benralizumab on the forced expiratory volume inone second (FEV₁) in adult subjects were examined.

BRIEF SUMMARY

Methods of increasing forced expiratory volume in one second (FEV₁) inan asthma patient are provided herein. In certain aspects, a method ofincreasing forced expiratory volume in one second (FEV₁) in an asthmapatient, comprises administering to the patient an effective amount ofbenralizumab or an antigen-binding fragment thereof.

Methods of treating asthma are also provided herein. In certain aspects,a method of treating asthma comprises administering to an asthma patientan effective amount of benralizumab or an antigen-binding fragmentthereof, wherein the patient has a blood eosinophil count of at least300 cells/μl prior to the administration.

In certain aspects, a method of treating asthma comprises administeringto an asthma patient an effective amount of benralizumab or anantigen-binding fragment thereof, wherein the patient has a forcedexpiratory volume in one second (FEV₁) of at least 75% predicted valueprior to the administration.

In certain aspects, a method of treating asthma comprises administeringat least two doses of benralizumab or an antigen-binding fragmentthereof to an asthma patient.

In certain aspects of the methods provided herein, the administrationincreases the patient's FEV₁. In certain aspects, the administrationincreases the patient's FEV₁ within 4 weeks of the first administration.In certain aspects, the FEV₁ is increased by at least 0.1 L. In certainaspects, the FEV₁ is increased by at least 0.13 L. In certain aspects,the FEV₁ is increased by at least 0.2 L. In certain aspects, the FEV₁ isincreased by at least 0.25 L. In certain aspects the FEV₁ is increasedby at least 0.50 L.

In certain aspects of the methods provided herein, the asthma iseosinophilic asthma. In certain aspects, the patient has a bloodeosinophil count of at least 300 cells/μl.

In certain aspects of the methods provided herein, the patient has aforced expiratory volume in one second (FEV₁) of at least 75% predictedvalue prior to the administration. In certain aspects, the patient hasan asthma control questionnaire score of at least 1.5 prior to theadministration. In certain aspects, the patient uses high-dose inhaledcorticosteroids (ICS). In certain aspects, the patient uses long-actingβ2 agonists (LABA). In certain aspects, the patient has a history ofexacerbations. In certain aspects, the history of exacerbationscomprises at least two exacerbations in the year prior to theadministration of benralizumab or an antigen-binding fragment thereof.In certain aspects, the history of exacerbations comprises no more thansix exacerbations in the year prior to the administration ofbenralizumab or an antigen-binding fragment thereof.

In certain aspects of the methods provided herein, at least two doses ofbenralizumab or an antigen-binding fragment thereof are administered tothe patient.

In certain aspects of the methods provided herein, benralizumab or anantigen-binding fragment thereof is administered at about 2 mg to about100 mg per dose. In certain aspects, benralizumab or an antigen-bindingfragment thereof is administered at about 20 mg per dose. In certainaspects, benralizumab or an antigen-binding fragment thereof isadministered at about 30 mg per dose. In certain aspects, benralizumabor an antigen-binding fragment thereof is administered at about 100 mgper dose.

In certain aspects of the methods provided herein, benralizumab or anantigen-binding fragment thereof is administered once every four weeksto once every twelve weeks. In certain aspects, benralizumab or anantigen-binding fragment thereof is administered once every four weeks.In certain aspects, benralizumab or an antigen-binding fragment thereofis administered once every eight weeks. In certain aspects, benralizumabor an antigen-binding fragment thereof is administered once every fourweeks for twelve weeks and then once every eight weeks.

In certain aspects of the methods provided herein, benralizumab or anantigen-binding fragment thereof is administered parenterally. Incertain aspects, benralizumab or an antigen-binding fragment thereof isadministered subcutaneously.

In certain aspects of the methods provided herein, benralizumab or anantigen-binding fragment thereof is administered in addition tocorticosteroid therapy.

In certain aspects, a method of increasing forced expiratory volume inone second (FEV₁) in an asthma patient comprises administering to thepatient 20-100 mg of benralizumab or an antigen-binding fragmentthereof, wherein the patient has an blood eosinophil count of at least300 cells/μl prior to the administration. In certain aspects, the methodcomprises administering 20 mg of benralizumab or an antigen-bindingfragment thereof. In certain aspects, the 20 mg of benralizumab isadministered once every four weeks for twelve weeks and then once everyeight weeks. In certain aspects, the method comprises administering 30mg of benralizumab or an antigen-binding fragment thereof. In certainaspects, the 30 mg of benralizumab is administered once every four weeksfor eight weeks and then once every eight weeks. In certain aspects, the30 mg of benralizumab is administered once every four weeks. In certainaspects, the method comprises administering 100 mg of benralizumab or anantigen-binding fragment thereof. In certain aspects, the 100 mg ofbenralizumab is administered once every four weeks for twelve weeks andthen once every eight weeks.

In certain aspects, a method of treating asthma in an asthma patientcomprises administering to the patient a dose of at least 2 and lessthan 100 mg of benralizumab or an antigen-binding fragment thereof. Incertain aspects, the method comprises administering 20 mg ofbenralizumab or an antigen-binding fragment thereof. In certain aspects,the method comprises administering 30 mg of benralizumab or anantigen-binding fragment thereof. In certain aspects, the methodcomprises administering a dose of at least 20 and less than 100 mg ofbenralizumab or an antigen-binding fragment thereof. In certain aspects,the method comprises administering a dose of at least 30 and less than100 mg of benralizumab or an antigen-binding fragment thereof. Incertain aspects, the method decreases exacerbation rates of asthma. Incertain aspects, the method decreases annual exacerbation rates ofasthma. In certain aspects, the administration is subcutaneous.

In certain aspects of the provided methods, administration ofbenralizumab or an antigen-binding fragment thereof results in theincrease in forced expiratory volume in one second (FEV₁) as shown inFIGS. 2-9.

In certain aspects of the provided methods, administration ofbenralizumab or an antigen-binding fragment thereof results in theincrease in forced expiratory volume in one second (FEV₁) as shown inExamples 1-2.

BRIEF DESCRIPTION OF THE DRAWINGS/FIGURES

FIG. 1 shows the study flow diagram.

FIG. 2 shows the change in forced expiratory volume in one second (FEV₁)at 24-weeks after treatment with placebo, 2 mg benralizumab, 20 mgbenralizumab, or 100 mg benralizumab in patients with fewer than 300eosinophils/μl and patients with at least 300 eosinophils/μl.

FIG. 3 shows the interim (24 weeks) and Stage I (52 weeks) change inFEV₁ after treatment with placebo, 2 mg benralizumab, 20 mgbenralizumab, or 100 mg benralizumab in patients with fewer than 300eosinophils/μl and patients with at least 300 eosinophils/μl

FIG. 4 shows the interim (24 weeks) and Stage I (52 weeks) change inFEV₁ after treatment with placebo, 2 mg benralizumab, 20 mgbenralizumab, or 100 mg benralizumab in patients with medium or high useof inhaled corticosteroids (ICS).

FIG. 5 shows the interim (24 weeks) and Stage I (52 weeks) change inFEV₁ after treatment with placebo, 2 mg benralizumab, 20 mgbenralizumab, or 100 mg benralizumab in patients with fewer than 300eosinophils/μl and (i) medium use of ICS or (ii) high use of ICS.

FIG. 6 shows the interim (24 weeks) and Stage I (52 weeks) change inFEV₁ after treatment with placebo, 2 mg benralizumab, 20 mgbenralizumab, or 100 mg benralizumab in patients with at least 300eosinophils/μl and (i) medium use of ICS or (ii) high use of ICS.

FIGS. 7A and 7B show the changes in FEV₁ in patients with variouseosinophil counts.

FIG. 8 shows the time course of mean FEV₁ in patients with at least 300eosinophils/μl.

FIG. 9 shows the time course of mean FEV₁ in patients with less than 300eosinophils/μl.

DETAILED DESCRIPTION

It is to be noted that the term “a” or “an” entity refers to one or moreof that entity; for example, “an anti-IL-5α antibody” is understood torepresent one or more anti-IL-5α antibodies. As such, the terms “a” (or“an”), “one or more,” and “at least one” can be used interchangeablyherein.

Provided herein are methods for increasing the forced expiratory volumein one second (FEV₁) in patients with asthma. The methods providedinclude administering an effective amount of benralizumab or anantigen-binding fragment thereof.

Information regarding benralizumab (or fragments thereof) for use in themethods provided herein can be found in U.S. Patent ApplicationPublication No. US 2010/0291073 A1, the disclosure of which isincorporated herein by reference in its entirety. Benralizumab andantigen-binding fragments thereof for use in the methods provided hereincomprise a heavy chain and a light chain or a heavy chain variableregion and a light chain variable region. In a further aspect,benralizumab or an antigen-binding fragment thereof for use in themethods provided herein includes any one of the amino acid sequences ofSEQ ID NOs: 1-4. In a specific aspect, benralizumab or anantigen-binding fragment thereof for use in the methods provided hereincomprises a light chain variable region comprising the amino acidsequence of SEQ ID NO:1 and a heavy chain variable region comprising theamino acid sequence of SEQ ID NO:3. In a specific aspect, benralizumabor an antigen-binding fragment thereof for use in the methods providedherein comprises a light chain comprising the amino acid sequence of SEQID NO: 2 and heavy chain comprising the amino acid sequence of SEQ IDNO:4. In a specific aspect, benralizumab or an antigen-binding fragmentthereof for use in the methods provided herein comprises a heavy chainvariable region and a light chain variable region, wherein the heavychain variable region comprises the Kabat-defined CDR1, CDR2, and CDR3sequences of SEQ ID NOs: 7-9, and wherein the light chain variableregion comprises the Kabat-defined CDR1, CDR2, and CDR3 sequences of SEQID NOs: 10-12. Those of ordinary skill in the art would easily be ableto identify Chothia-defined, Abm-defined or other CDRs. In a specificaspect, benralizumab or an antigen-binding fragment thereof for use inthe methods provided herein comprises the variable heavy chain andvariable light chain CDR sequences of the KM1259 antibody as disclosedin U.S. Pat. No. 6,018,032, which is herein incorporated by reference inits entirety.

In certain aspects, a patient presenting at a physician's office or EDwith asthma is administered benralizumab or an antigen-binding fragmentthereof. Given the ability of benralizumab to reduce or depleteeosinophil counts for up to 12 weeks or more (see US 2010/0291073),benralizumab or an antigen-binding fragment thereof can be administeredonly once or infrequently while still providing benefit to the patientin increasing the forced expiratory volume in one second (FEV₁). Infurther aspects the patient is administered additional follow-on doses.Follow-on doses can be administered at various time intervals dependingon the patient's age, weight, ability to comply with physicianinstructions, clinical assessment, eosinophil count (blood or sputumeosinophils), Eosinophilic Cationic Protein (ECP) measurement,Eosinophil-derived neurotoxin measurement (EDN), Major Basic Protein(MBP) measurement and other factors, including the judgment of theattending physician. The intervals between doses can be every fourweeks, every five weeks, every 6 weeks, every 8 weeks, every 10 weeks,every 12 weeks, or longer intervals. In certain aspects the intervalsbetween doses can be every 4 weeks, every 8 weeks or every 12 weeks. Incertain aspects, the single dose or first dose is administered to theasthma patient shortly after the patient presents with an acuteexacerbation, e.g., a mild, moderate or severe exacerbation. Forexample, the single or first dose of benralizumab or an antigen-bindingfragment thereof can be administered during the presenting clinic orhospital visit, or in the case of very severe exacerbations, within 1,2, 3, 4, 5, 6, 7, or more days, e.g., 7 days of the acute exacerbation,allowing the patient's symptoms to stabilize prior to administration ofbenralizumab.

In some embodiments, at least two doses of benralizumab orantigen-binding fragment thereof are administered to the patient. Insome embodiments, at least three doses, at least four doses, at leastfive doses, at least six doses, or at least seven doses are administeredto the patient. In some embodiments, benralizumab or an antigen-bindingfragment thereof is administered over the course of four weeks, over thecourse of eight weeks, over the course of twelve weeks, over the courseof twenty-four weeks, or over the course of a year.

The amount of benralizumab or an antigen-binding fragment thereof to beadministered to the patient will depend on various parameters such asthe patient's age, weight, clinical assessment, eosinophil count (bloodor sputum eosinophils), Eosinophilic Cationic Protein (ECP) measurement,Eosinophil-derived neurotoxin measurement (EDN), Major Basic Protein(MBP) measurement and other factors, including the judgment of theattending physician. In certain aspects, the dosage or dosage intervalis not dependent on the sputum eosinophil level.

In certain aspects the patient is administered one or more doses ofbenralizumab or an antigen-binding fragment thereof wherein the dose isabout 2 mg to about 100 mg, for example about 20 mg to about 100 mg, orabout 30 mg to about 100 mg. In certain specific aspects, the patient isadministered one or more doses of benralizumab or an antigen-bindingfragment thereof where the dose is about 20 mg, about 30 mg, about 40mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, orabout 100 mg. In some embodiments, the dose is about 20 mg. In someembodiments the dose is about 30 mg. In some embodiments, the dose isabout 100 mg.

In certain aspects, administration of benralizumab or an antigen-bindingfragment thereof according to the methods provided herein is throughparenteral administration. For example, benralizumab or anantigen-binding fragment thereof can be administered by intravenousinfusion or by subcutaneous injection.

In certain aspects, benralizumab or an antigen-binding fragment thereofis administered according to the methods provided herein in combinationor in conjunction with additional asthma therapies. Such therapiesinclude, without limitation, inhaled corticosteroid therapy, long- orshort-term bronchodilator treatment, oxygen supplementation, or otherstandard therapies as described, e.g., in the NAEPP Guidelines. Incertain aspects, use of the methods provided herein, i.e.,administration of benralizumab or an antigen-binding fragment thereof toan asthma patient with a history of acute exacerbations serves asadjunct therapy in situations of poor compliance with standard forms ofasthma management.

The methods provided herein can significantly increase forced expiratoryvolume in one second (FEV₁) in asthmatics. An increase can be measuredbased on the expected FEV₁ based on a large patient population, on theFEV₁ measured in a control population, or on the individual patient'sFEV₁ prior to administration. In certain aspects, the patient populationis those patients who had ≧2 exacerbations requiring oral systemiccorticosteroids in the past year. In certain aspects, the patientpopulation is those patients who had ≧2 exacerbations requiring systemiccorticosteroid bursts in the past year and ≦6 exacerbations requiringsystemic corticosteroid bursts in the past year. In certain aspects, thepatient population is patients having an eosinophil count of at least300 cells/μl.

In certain aspects, use of the methods provided herein, i.e.,administration of benralizumab or an antigen-binding fragment thereofincreases the forced expiratory volume in one second (FEV₁) over a24-week period following administration of benralizumab or anantigen-binding fragment thereof, as compared to the patient's baselineFEV₁. In certain aspects, the patient can receive follow on doses ofbenralizumab or an antigen-binding fragment thereof at periodicintervals, e.g., every 4 weeks, every 5 weeks, every 6 weeks, every 8weeks, every 12 weeks, or as scheduled based on patient's age, weight,ability to comply with physician instructions, clinical assessment,eosinophil count (blood or sputum eosinophils), Eosinophilic CationicProtein (ECP) measurement, Eosinophil-derived neurotoxin measurement(EDN), Major Basic Protein (MBP) measurement and other factors,including the judgment of the attending physician. Use of the methodsprovided herein can increase FEV₁ by at least 0.05 L, at least 0.1 L, atleast 0.13 L, at least 0.15 L, at least 0.20 L, at least 0.21 L, atleast 0.22 L, at least 0.23 L, at least 0.24 L, or at least 0.25 L, atleast 0.30 L, at least 0.35 L, at least 0.40 L, at least 0.45 L, or atleast 0.50 L over the 24-week period.

In other aspects, use of the methods provided herein, i.e.,administration of benralizumab or an antigen-binding fragment thereof toan asthma patient, increases the forced expiratory volume in one second(FEV₁) of patient over a 52-week period following administration of thebenralizumab or antigen-binding fragment thereof. In certain aspects,the patient can receive follow on doses of benralizumab or anantigen-binding fragment thereof at periodic intervals, e.g., every 4weeks, every 5 weeks, every 6 weeks, every 8 weeks, every 12 weeks, oras scheduled based on patient's age, weight, ability to comply withphysician instructions, clinical assessment, eosinophil count (blood orsputum eosinophils), Eosinophilic Cationic Protein (ECP) measurement,Eosinophil-derived neurotoxin measurement (EDN), Major Basic Protein(MBP) measurement and other factors, including the judgment of theattending physician. In certain aspects, the interval is every 4 weeks,every 8 weeks or every 12 weeks. Use of the methods provided herein canincreases the forced expiratory volume in one second (FEV₁) by at least0.05 L, at least 0.1 L, at least 0.13 L, at least 0.15 L, at least 0.20L, at least 0.21 L, at least 0.22 L, at least 0.23 L, at least 0.24 L,or at least 0.25 L, at least 0.30 L, at least 0.35 L, at least 0.40 L,at least 0.45 L, or at least 0.50 L over the 24-week period.

In certain aspects, use of the methods provided herein, i.e.,administration of benralizumab or an antigen-binding fragment thereofincreases the forced expiratory volume in one second (FEV₁) within 4weeks, within 8 weeks, within 12 weeks, within 16 weeks, within 20weeks, within 24 weeks, within 28 weeks, within 32 weeks, within 36weeks, within 40 weeks, within 44 weeks, within 48 weeks, or within 52weeks.

In certain aspects, use of the methods provided herein, i.e.,administration of benralizumab or antigen-binding fragment thereof to anasthma patient, increases forced expiratory volume in one second (FEV₁),reduces the annual exacerbation rate, and/or improves an asthmaquestionnaire score (e.g., the asthma control questionnaire (ACQ)).

In certain aspects, the patient is “eosinophilic positive” meaning thepatient is one whose asthma is likely to be eosinophilic.

In certain aspects, the asthma patient has a particular blood eosinophilcount, e.g., prior to the administration of benralizumab or anantigen-binding fragment thereof. Blood eosinophil counts can bemeasured, for example, using a complete blood count (CBC) with celldifferential.

In certain aspects, the asthma patient has a blood eosinophil count ofat least 300 cells/μl prior to the administration of benralizumab or anantigen-binding fragment thereof. In certain aspects, the asthma patienthas a blood eosinophil count of at least 350 cells/μl, at least 400cells/μl, at least 450 cells/μl, or at least 500 cells/μl prior to theadministration of benralizumab or an antigen-binding fragment thereof.

In certain aspects, the asthma patient has a blood eosinophil count ofless than 300 cells/μl prior to the administration of benralizumab or anantigen-binding fragment thereof. In certain aspects, the asthma patienthas a blood eosinophil count of at least 100 cells/μl, at least 150cells/μl, at least 180 cells/μl, at least 200 cells/μl, or at least 250cells/μl prior to the administration of benralizumab or anantigen-binding fragment thereof.

In certain aspects, the asthma patient was prescribed or has been usinga medium-dose of inhaled corticosteroids (ICS) use prior to theadministration of benralizumab or an antigen-binding fragment thereof. Amedium-dose of ICS can be a dose of at least 600 μg to 1,200 μgbudesonide daily or an equivalent dose of another ICS.

In certain aspects, the asthma patient was prescribed or had been usinga high-dose of ICS use prior to the administration of benralizumab or anantigen-binding fragment thereof. A high-dose of ICS can be a dose of atleast 1,200 μg budesonide daily or an equivalent dose of another ICS. Ahigh dose of ICS can also be a dose of greater than 1,200 μg to 2000 μgbudesonide daily or an equivalent dose of another ICS.

In certain aspects, the asthma patient was prescribed or has been usingoral corticosteroids prior to the administration of benralizumab or anantigen-binding fragment thereof. In certain aspects, administration ofbenralizumab or an antigen-binding fragment thereof decreases the use oforal corticosteroids in an asthma patient. In certain aspects, theadministration decreases the use of oral corticosteroids in an asthmapatient by at least 50%.

In certain aspects, the asthma patient was prescribed or had been usinga long-acting beta agonist (LAB A) prior to the administration ofbenralizumab or an antigen-binding fragment thereof.

In certain aspects, the asthma patient was prescribed or had been usingboth ICS and LABA prior to the administration of benralizumab or anantigen-binding fragment thereof.

In certain aspects, the asthma patient has a blood eosinophil count ofat least 300 cells/μl and high ICS use prior to the administration ofbenralizumab or an antigen-binding fragment thereof.

In certain aspects, the asthma patient has a forced expiratory volume in1 second (FEV₁) of at least 40% and less than 90% predicted value priorto the administration of benralizumab or an antigen-binding fragmentthereof. In some embodiments, the FEV₁ is greater than 70% predictedvalue prior to the administration of benralizumab or an antigen-bindingfragment thereof. In some embodiments, the FEV₁ is greater than 70% andless than 90% predicted value prior to the administration ofbenralizumab or an antigen-binding fragment thereof. In someembodiments, the FEV₁ is at least 75% predicted value prior to theadministration of benralizumab or an antigen-binding fragment thereof.In some embodiments, the FEV₁ is at least 75% and less than 90% priorpredicted value to the administration of benralizumab or anantigen-binding fragment thereof. In some embodiments, the FEV₁ is atleast 80% predicted value prior to the administration of benralizumab oran antigen-binding fragment thereof. In some embodiments, the FEV₁ is atleast 80% and less than 90% predicted value prior to the administrationof benralizumab or an antigen-binding fragment thereof.

EXAMPLES Example 1 Patients and Methods (a) Subjects

Subjects in this study were required to be 18 to 75 years of age with aweight of greater than 45 kg and less than or equal to 150 kg (greaterthan 100 pounds, but less than or equal to 330 pounds). They also musthave had a physician diagnosis of asthma for a minimum of 12 monthsprior to screening as well as physician prescribed daily use ofmedium-dose or high-dose inhaled corticosteroids (ICS) plus long-actingbeta agonist (LABA) or any combination of sequential dosing of eithermedium-dose or high-dose ICS/LABA for at least 12 months prior toscreening. Medium and high-doses of ICS as defined in this study areshown in Table 1 below.

TABLE 1 Estimated Comparative Daily Dosages for Inhaled CorticosteroidsMedium Daily High Daily Drug Dose (Adult) Dose (Adult) BeclamethazoneHFA/MDI 40 or 80 μg/puff >240-480 μg >480 μg Budesonide DPI 90, 180, or200 μg/inhalation >600-1,200 μg >1,200 μg Ciclesonide HFA/MDI 80 or 160μg/inhalation >160-320 μg >320-1280 μg Flunisolide CFC/MDI 250μg/puff >1,000-2,000 μg >2,000 μg Flunisolide HFA/MDI 80μg/puff >320-640 μg >640 μg Fluticasone HFA/MDI: 44, 110, or 220μg/puff >264-440 μg >440 μg DPI: 50, 100, or 250 μg/puff >300-500μg >500 μg Mometasone DPI 200 μg/inhalation 400 μg >400 μg Triamcinoloneacetonide CFC/MDI 75 μg/puff >750-1,500 μg >1,500 μg CFC =chlorofluorocarbon; DPI = dry powder inhaler; HFA = hydrofluoroalkane;MDI = metered dose inhaler.

The dose of other asthma controller medications must have been stable inthe subjects for at least 30 days prior to screening. Subjects must alsohave had at least 2, but no more than 6, documented asthma exacerbationsin the 12 months prior to screening that required the use of a systemiccorticosteroid burst. Subjects must also have had a morningpre-bronchodilator forced expiratory volume in 1 second (FEV₁) of atleast 40% and less than 90% predicted during the screening/run-in period(described below). Subjects must also have fulfilled one of thefollowing criteria:

-   a) Proof of post-bronchodilator reversibility of airflow    obstruction≧12% and ≧200 mL documented within 36 months prior to    randomization or proof of a positive response [PC20≦8 mg/mL] to a    methacholine challenge documented within 36 months prior to    randomization; OR-   b) A post-bronchodilator increase in FEV₁≧12% and ≧200 mL at Week −3    screening visit; OR-   c) If a) and b) were not met and all other inclusion/exclusion    criteria were met, subjects with a FEV₁ of ≧1.5 L and ≧60% predicted    on the Week −2 screening visit were eligible to undergo a    methacholine challenge at the Week −2 screening visit at sites where    methacholine testing was available. If the subject achieved a    positive response, (PC20≦8 mg/mL), then this inclusion criterion was    met.

Subjects must also have had an Asthma Control Questionnaire (ACQ) scoreof at least 1.5 at least twice during the screening/run-in period.

Subjects were not able to participate if they had a cigarette exposureof 10 pack-years or more or had been smoking within 12 months prior toscreening or had any condition (e.g., any eosinophilic lower respiratorydisease other than asthma, chronic obstructive pulmonary disease (COPD),or cystic fibrosis) that, in the opinion of the investigator or medicalmonitor, would interfere with the evaluation. Subjects were also notable to participate if they had received an oral corticosteroid burst orshort-acting systemic corticosteroid within 30 days prior to screeningor during the screening/run-in period.

(b) Design of the Study

The study was a phase 2b randomized, double-blind, placebo-controlled,dose-ranging, multicenter study (ClinicalTrials.gov number: NCT01238861)in which multiple doses of benralizumab were administered subcutaneouslyto asthma patients. Benralizumab was administered at 2, 20, or 100 mgdoses, and patients were followed for 1 year. The study flow diagram isshown in FIG. 1.

A 3-week screening/run-in period preceded administration of benralizumabor placebo. During the 3-week period, subjects continued to use the samemedium-dose or high-dose ICS/LABA combination product as prior to theparticipation in the study (doses of ICS/LABA were required to be stablefor 30 days prior to the 3-week screening/run-in period). Subjectsremained on the same dose of ICS/LABA throughout the study.

The administered benralizumab composition contained benralizumab (50mg/mL), 10 mM histidine, 10 mM histidine HCl monohydrate, 9% (w/v)trehalose dihydrate, and 0.004% (w/v) polysorbate-20, pH 6. Theadministered placebo composition contained 10 mM histidine, 10 mMhistidine hydrochloride monohydrate, 9% (w/v) trehalose dihydrate, and0.02% (w/v) polysorbate-20, pH 6.

Subjects received two subcutaneous (SC) injections of 1 ml ofbenralizumab or placebo every four weeks for the first 3 doses on Weeks1 (Day 1), 4, and 8 and then every 8 weeks thereafter for the last 4doses on Weeks 16, 24, 32, and 40. After Week 40, subjects were followedfor an additional 12 weeks (through Week 52) for assessment of acuteexacerbations. The day of receipt of the first dose of benralizumab orplacebo was considered Day 1.

Pulmonary function as measured by changes of airflow obstruction (FEV₁and forced vital capacity (FVC) at the site and peak expiratory flow(PEF) and FEV₁ at home) during the study was assessed. The measurements,along with change from baseline at various time points were summarizedusing descriptive statistics. ANCOVA with treatment arm and baselinevalue as possible covariates were used to compare the changes frombaseline in FEV₁ and PEF between the individual benralizumab group andthe placebo group, respectively.

Home peak flow testing for FEV₁ and PEF were performed twice daily inthe morning upon awakening and in the evening prior to bedtime from thefirst screening visit through the Week 52 visit using an ePRO device.Subject adherence was checked at each visit through the Week 52 visit.Subjects were asked to perform peak flow testing every morning whilesitting or standing, but in the same position at every testing. Peakflow meters for home and instructions for data recording were providedto each enrolled subject at screening.

In addition, spirometry was performed by the investigator or qualifieddesignee on equipment provided by a central vendor according toATS/European Respiratory Society (ERS) guidelines (Miller et al, EurRespir J 26:153-61 (2005)). Spirometry was performed at weeks −3, −2,−1, 1 (Day 1), 4, 16, 24, 32, 40, and 52 in the morning between 6:00 AMand 11:00 AM. On treatment days, spirometry testing was performed beforeadministration of investigational product. All post-screening morningspirometry testing was required to be completed between 6 and 11 AM andwithin ±1 hour of the time the screening spirometry was completed. Forexample, if the screening spirometry was at 8:00 AM, then all subsequentspirometry testing needed to be completed between 7:00 AM and 9:00 AM.

Multiple forced expiratory efforts (at least 3 but no more than 8) wereperformed for each office spirometry session, and the 2 best effortsthat meet the American Thoracic Society/European Respiratory Society(ATS/ERS) acceptability and reproducibility criteria were recorded. Thebest efforts were based on the highest FEV₁. The maximum FEV₁ of the 2best efforts was used for the analysis. The absolute measurement (forFEV₁ and forced vital capacity (FVC)), and the percentage of predictednormal value (Hankinson et al., Am J Respir Crit Care Med 159:179-87(1999)) was recorded. The highest FVC was also reported regardless ofthe effort in which it occurred (even if the effort did not result inthe highest FEV₁). The preferred standard for predicted normal ranges isthe National Health and Nutrition Examination Survey III (NHANES III).Indirect measurement of air trapping was assessed using data obtainedfrom routine spirometry. The spirometry data will be input into theformula developed by Sorkness et al. (J Appl Physiol 104:394-403(2008)).

Reversibility of FEV₁ with albuterol/salbutamol was measured at weeks−3, 1 (Day 1), 16, 24, 32, 40, and 52 after the subject has performedpre-bronchodilator (pre-BD) spirometry. Maximal bronchodilation wereinduced using albuterol/salbutamol MDI with an Aeorchamber for a maximumof 8 total puffs or 720 μg (Sorkness et al., J Appl Physiol 104:394-403(2008)).

Following pre-BD spirometry, 4 puffs of albuterol/salbutamol MDI wasadministered in single puffs 30 seconds apart and post-bronchodilator(post-BD) spirometry was performed 15-20 minutes later. Afterwards, anadditional 2 puffs of albuterol/salmeterol was administered in singlepuffs 30 seconds apart and a second post-BD spirometry was performed15-20 minutes later. Finally, if the incremental change in FEV₁ after 6puffs of albuterol/salbutamol was ≦5% the FEV₁ value after 4 puffs ofalbuterol/salbutamol, then last 2 puffs of albuterol/salmeterol were notadministered. On the other hand, if the change is >5% then 2 puffs ofalbuterol/salmeterol was administered in single puffs 30 seconds apartand a third post-BD spirometry was performed 15-20 minutes later.

The % difference comparing FEV₁ after 6 puffs to the FEV₁ after 4 puffswas calculated as follows:

% Difference=(FEV₁(6 puffs)−FEV₁ (4 puffs)/FEV₁ (4 puffs)×100

The highest pre- and post-BD FEV₁ were used to determine reversibility,which was calculated as follows:

% Reversibility=(post-BD FEV1−pre-BD FEV₁)×100/pre-BD FEV₁

The methacholine inhalation challenge was completed in the morning ±1hour at each assessment, if applicable. Direct challenges usingmethacholine cause airflow obstruction by acting directly on airwaysmooth muscle to reduce FEV₁. Methacholine inhalation challenge testingwas performed using either of 2 ATS guideline recommended methodologies:the 2-minute tidal breathing method or the 5 breath dosimeter method(American Thoracic Society, Am J Respir Crit Care Med. 161:309-329(2000)). The same method was used on individual subjects. At each stagethe maximum FEV₁ determined the best effort; the highest FVC and peakflow were also recorded even if they were obtained in different effortsfrom the maximum FEV₁. Only 2 efforts were required at each stage ifthese efforts were considered by the investigator or qualified designeeto be representative of the subject's ability to perform spirometry atthat stage. In general, no more than 3 efforts were performed at eachstage in order to conserve the subject's ability to perform spirometryfor the duration of the test.

Contraindications for methacholine challenge testing included:pregnancy, breast feeding, FEV₁<1.5 L or <60% of predicted, heart attackor stroke in the previous 3 months, known aortic aneurysm, uncontrolledhypertension (systolic>200 mm Hg or diastolic>100 mm Hg), current use ofanticholinesterase medication for myasthenia gravis, respiratoryinfection in the previous 6 weeks, acute asthma attack on day of study,oral corticosteroid burst in the previous 30 days, or certain prohibitedmedication or food.

The fall in FEV₁ was calculated as a percentage of the best FEV₁determined at the saline stage. Subjects with a positive test or whowere symptomatic received 2-4 puffs of albuterol/salbutamol and wereobserved until their FEV₁ returned to at least 90% of the baseline (Week-2 screening visit) value. Subjects who had a decrease in FEV₁ of >50%were rescued with albuterol and followed closely. If the FEV₁ did notreturn to at least 90% of baseline (pre-diluent) value, the subject wasnot be discharged from the clinic without the approval of theinvestigator or qualified designee.

(c) Safety Assessments

Adverse events were monitored following administration of placebo orbenralizumab. Other assessments included physical examination, vitalsign monitoring, and laboratory measurements.

Example 2 Results (a) Enrollment and Baseline Characteristics

The baseline characteristics of all randomized subjects who received anydose of investigational product are provided in Table 2 below. The meanpopulation ICS dose was 1100 budesonide equivalents overall, 700budesonide equivalents in the medium dose stratum, and 1600 budesonideequivalents in the high dose stratum.

TABLE 2 Demographics for Baseline Eosinophils (EOS) PLACEBO BENRALIZUMABPLACEBO BENRALIZUMAB POPULATION EOS < 300 EOS < 300 EOS >= 300 EOS >=300 N 139 151 83 232 Mean Age (yrs) 50.3 51.2 45.2 46.3 Gender Female(%) 71 70 66 68 Race White (%) 76 80 64 65 BMI (mean) 29.6 29.2 28.828.5 EOS mean cells/μl 149 156 542 548-615 Chronic OCS (%)  2.2%  7.9% 4.8%  4.3% FEV₁ (L) % pred 70.0 54-69 65 64-67 Reversibility (%) 12.513-18 15.5 17-19 Historical 2.2 2.3-2.5 2.2 2.3-2.5 Exacerbations ACQ atBaseline 2.5 2.5-2.8 2.6 2.4-2.7 Childhood   32%   33-38%   40%   37-41%Asthma YES History Nasal 10.8% 11.9% 14.5% 19.3% Polyps YES FE_(NO) meanppb 22.1 21-39 34.8 34-42 OCS = oral corticosteroids; FEV₁ = forcedexpiratory volume in 1 second; ACQ = asthma control questionnaire; andFENO = fraction of exhaled nitric oxide.

The baseline characteristics of randomized subjects who received anydose of investigational product and had a baseline eosinophil count ofat least 300 cells/μl are shown in Table 3 below.

TABLE 3 Demographics for ICS with Baseline EOS at Least 300 Cells/μlPLACEBO BENRALIZUMAB PLACEBO BENRALIZUMAB POPULATION MED ICS MED ICSHIGH ICS HIGH ICS N 43 121 40 111 Mean Age (yrs) 45 46-47 45 45-47Gender Female (%) 65 63 68 70-79 Race White (%) 56 66 73 63 BMI (mean)27.3 27.6-28.3 30.3 27.8-30.0 EOS mean cells/μl 480 462-625 608 605-656Chronic OCS (%) 0 0 10% 9% FEV₁ (L) % pred 68.8 64-70 60 63-65Reversibility (%) 16%   17-23% 15%   14-21% Historical 2.2 2.1-2.5 2.32.4-2.5 Exacerbations ACQ at Baseline 2.6 2.3-2.6 2.7 2.6-2.8 Childhood42% 36% 38%   27-53% Asthma YES History Nasal 14% 11% 15%   23-37%Polyps YES FE_(NO) mean ppb 38.3 35-45 31.0 33-39 OCS = oralcorticosteroids; FEV₁ = forced expiratory volume in 1 second; ACQ =asthma control questionnaire; and FENO = fraction of exhaled nitricoxide.

(b) Efficacy

The effects of administration of benralizumab on FEV₁ are shown in FIGS.2-9. For example, the data in FIG. 2 demonstrate that by week 24,patients with a blood eosinophil count of at least 300 cells/μl whoreceived 2, 20, or 100 mg of benralizumab showed increases in FEV₁.Similar results were also observed at week 52 (FIG. 3). The data in FIG.4 demonstrate that FEV₁ was improved in patients receiving either mediumor high dose ICS, but the improvement was greater in patients receivinghigh dose ICS. The data in FIG. 5 compare the changes in FEV₁ inpatients with a blood eosinophil count of less than 300 cells/μl whowere receiving medium dose ICS with those receiving high dose ICS, andthe data in FIG. 6 compare the changes in FEV₁ in patients with a bloodeosinophil count of at least 300 cells/μl who were receiving medium doseICS with those receiving high dose ICS. In patients with a bloodeosinophil count of at least 300 cells/μl, a greater improvement in FEV₁was observed in those receiving a high dose of ICS (FIG. 6). A moredetailed breakdown by eosinophil number is provided in FIG. 7. As shownin FIGS. 8 and 9, a difference in FEV₁ between patients receivingbenralizumab and placebo was observable as early as week 4. However,this difference was much greater in patients with a blood eosinophilcount of at least 300 cells/μl.

(c) Safety

Treatment emergent adverse events (TEAEs) occurred at an approximate 10percentage point higher frequency in patients treated with benralizumabcompared with those treated with placebo. Treatment emergent severeadverse events (TE-SAEs) occurred at similar frequencies in patientstreated with benralizumab and placebo. TEAEs and TE-SAEs were not dosedependent in patients treated with benralizumab.

(d) Anti-Drug Antibodies

The development of anti-drug antibodies (ADA) to benralizumab wasinversely related to dose, with the highest proportion of ADA-positivesubjects at the 2 mg dose (see Table 4 below). The incidence of hightiter ADA (≧400) was 12% and 9% in the 20 and 100 mg dose groups,respectively. High titer ADAs were associated with reduced benralizumabconcentration and varying degrees of eosinophil recovery when present.The pharmacokinetic/pharmacodynamic (PK/PD) impact of high titer ADA wasreduced at higher drug exposures. No pattern was observed between TEAEsand ADA.

TABLE 4 Anti-Drug Antibodies at Week 24 % Subjects % Subjects TotalNumber with Positive with ADA Treatment Group of Subjects ADA TitresTitres ≧ 400 Placebo 222  8.1% (n = 18) 3% (n = 6) Benralizumab 2 mg 8134.6% (n = 28) 23% (n = 19) Benralizumab 20 mg 81 18.5% (n = 15) 12% (n= 10) Benralizumab 100 mg 222 21.2% (n = 47)  9% (n = 20)

Based on both PK and immunological considerations, additional patientswill receive dosing of 30 mg benralizumab. In some patients, the 30 mgbenralizumab dose will be administered every four weeks. In somepatients, the 30 mg benralizumab dose will be administered once everyfour weeks for three doses and then once every eight weeks thereafter.

(e) Discussion

This study demonstrates that benralizumab improves lung function.Improvements were observed at all doses, but a greater magnitude ofbenefit was evident in the 20 and 100 mg doses relative to the 2 mgdose. In addition, FEV₁ appeared to improve more in those on high-doseICS/LABA than those on medium-dose ICS/LABA.

Example 3 Additional Dose Evaluation

Dose-efficacy modeling was performed to identify additional doses ofbenralizumab that reduce annual exacerbation rates and are safe and welltolerated. The modeling indicated that a dose of about 30 mg is theminimum effective dose to produce 90% maximum treatment effect.Therefore patients with uncontrolled asthma receive subcutaneousinjections of 30 mg of benralizumab or placebo. The 30 mg doses areadministered (i) every four weeks or (ii) every four weeks for eightweeks (3 doses) and then every eight weeks (i.e., every 8 weeksincluding an additional dose at week 4). The number of exacerbations inpatients receiving 30 mg benralizumab is compared to the number ofexacerbations in patients receiving placebo in order to demonstrate that30 mg doses of benralizumab decrease annual exacerbation rates. Inaddition, the number of exacerbations in patients with baseline bloodeosinophil count of at least 300 cells/μl is analyzed in order todemonstrate that 30 mg doses of benralizumab can be effective indecrease annual exacerbation rates in such patients.

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents to the specificaspects of the disclosure described herein. Such equivalents areintended to be encompassed by the following claims.

Various publications are cited herein, the disclosures of which areincorporated by reference in their entireties.

Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity ofunderstanding, it will be obvious that certain changes and modificationscan be practiced within the scope of the appended claims.

SEQUENCE LISTING SEQ ID NO: 1<US20100291073_1 Sequence 1 from Patent US 20100291073 Organism: Homo sapiensDIQMTQSPSSLSASVGDRVTITCGTSEDIINYLNWYQQKPGKAPKLLIYHTSRLQSGVPSRFSGSGSGTDFTLTISSLQP EDFATYYCQQGYTLPYTFGQGTKVEIK SEQ ID NO: 2<US20100291073_2 Sequence 2 from Patent US 20100291073 Organism: Homo sapiensDIQMTQSPSSLSASVGDRVTITCGTSEDIINYLNWYQQKPGKAPKLLIYHTSRLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQGYTLPYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 3<US20100291073_3 Sequence 3 from Patent US 20100291073 Organism: Homo sapiensEVQLVQSGAEVKKPGASVKVSCKASGYTFTSYVIHWVRQRPGQGLAWMGYINPYNDGTKYNERFKGKVTITSDRSTSTVY MELSSLRSEDTAVYLCGREGIRYYGLLGDYWGQGTLVTVSSSEQ ID NO: 4<US20100291073_4 Sequence 4 from Patent US 20100291073 Organism: Homo sapiensEVQLVQSGAEVKKPGASVKVSCKASGYTFTSYVIHWVRQRPGQGLAWMGYINPYNDGTKYNERFKGKVTITSDRSTSTVYMELSSLRSEDTAVYLCGREGIRYYGLLGDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPP VLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKSEQ ID NO: 5<US20100291073_5 Sequence 5 from Patent US 20100291073 Organism: Homo sapiensDLLPDEKISLLPPVNFTIKVTGLAQVLLQWKPNPDQEQRNVNLEYQVKINAPKEDDYETRITESKCVTILHKGFSASVRTILQNDHSLLASSWASAELHAPPGSPGTSIVNLTCTTNTTEDNYSRLRSYQVSLHCTWLVGTDAPEDTQYFLYYRYGSWTEECQEYSKDTLGRNIACWFPRTFILSKGRDWLAVLVNGSSKHSAIRPFDQLFALHAIDQINPPLNVTAEIEGTRLSIQWEKPVSAFPIHCFDYEVKIHNTRNGYLQIEKLMTNAFISIIDDLSKYDVQVRAAVSSMCREAGLWSEWSQPIYVGNDEHKPLREWFVIVIMATICFILLILSLICKICHLWIKLFPPIPAPKSNIKDLFVTTNYEKAGSSETEIEVICYIEKPGVETLEDSVF SEQ ID NO: 6<US20100291073_6 Sequence 6 from Patent US 20100291073 Organism: Mus musculusDLLNHKKFLLLPPVNFTIKATGLAQVLLHWDPNPDQEQRHVDLEYHVKINAPQEDEYDTRKTESKCVTPLHEGFAASVRTILKSSHTTLASSWVSAELKAPPGSPGTSVTNLTCTTHTVVSSHTHLRPYQVSLRCTWLVGKDAPEDTQYFLYYRFGVLTEKCQEYSRDALNRNTACWFPRTFINSKGFEQLAVHINGSSKRAAIKPFDQLFSPLAIDQVNPPRNVTVEIESNSLYIQWEKPLSAFPDHCFNYELKIYNTKNGHIQKEKLIANKFISKIDDYSTYSIQVRAAVSSPCRMPGRWGEWSQPIYVGKERKSLVEWHLIVLPTAACFVLLIFSLICRVCHLWTRLFPPVPAPKSNIKDLPVVTEYEKPSNETKIEVVHCVEEVGFEVMGNSTF SEQ ID NO: 7-VH CDR1 SYVIH SEQ ID NO: 8-VH CDR2YINPYNDGTKYNERFKG SEQ ID NO: 9-VH CDR3 EGIRYYGLLGDYSEQ ID NO: 10-VL CDR1 GTSEDIINYLN SEQ ID NO: 11-VL CDR2 HTSRLQSSEQ ID NO: 12-VL CDR3 QQGYTLPYT

1. A method of increasing forced expiratory volume in one second (FEV1)in an asthma patient, comprising administering to the patient aneffective amount of benralizumab or an antigen-binding fragment thereof,wherein the administration increases the patient's FEV
 1. 2. A method oftreating asthma, comprising administering to an asthma patient aneffective amount of benralizumab or an antigen-binding fragment thereof,wherein the patient has a blood eosinophil count of at least 300cells/μl prior to the administration.
 3. A method of treating asthma,comprising administering to an asthma patient an effective amount ofbenralizumab or an antigen-binding fragment thereof, wherein the patienthas a forced expiratory volume in one second (FEV1) of at least 75%predicted value prior to the administration.
 4. (canceled)
 5. The methodof claim 2, wherein the administration increases the patient's FEV
 1. 6.The method of claim 5, wherein the administration increases thepatient's FEV1 within 4 weeks of the first administration.
 7. The methodof claim 1, wherein the asthma is eosinophilic asthma.
 8. The method ofclaim 1, wherein the patient has a blood eosinophil count of at least300 cells/μl.
 9. The method of claim 1, wherein, the patient has aforced expiratory volume in one second (FEV1) of at least 75% predictedvalue prior to the administration.
 10. (canceled)
 11. (canceled)
 12. Themethod of claim 1, which increases the patient's FEV1 followingadministration of the benralizumab or antigen-binding fragment thereof.13. The method of claim 1, wherein the FEV1 is increased by at least 0.1L.
 14. (canceled)
 15. (canceled)
 16. (canceled)
 17. (canceled)
 18. Themethod of claim 1, wherein the patient uses high-dose inhaledcorticosteroids (ICS).
 19. The method of claim 1, wherein the patientuses long-acting β2 agonists (LABA).
 20. The method of claim 1, whereinthe patient has a history of exacerbations.
 21. (canceled) 22.(canceled)
 23. The method of claim 1, wherein the benralizumab orantigen-binding fragment thereof is administered at about 2 mg to about100 mg per dose.
 24. The method of claim 23, wherein the benralizumab orantigen-binding fragment thereof is administered at about 20 mg perdose.
 25. The method of claim 23, wherein the benralizumab orantigen-binding fragment thereof is administered at about 30 mg perdose.
 26. The method of claim 23, wherein the benralizumab orantigen-binding fragment thereof is administered at about 100 mg perdose.
 27. The method of claim 1, wherein the benralizumab orantigen-binding fragment thereof is administered once every four weeksto once every twelve weeks.
 28. (canceled)
 29. (canceled)
 30. The methodof claim 27, wherein the benralizumab or antigen-binding fragmentthereof is administered once every four weeks for twelve weeks and thenonce every eight weeks.
 31. (canceled)
 32. (canceled)
 33. The method ofclaim 1, wherein the benralizumab or antigen-binding fragment thereof isadministered in addition to corticosteroid therapy. 34-49. (canceled)